This project will use functional magnetic resonance imaging (fMRI) to characterize dysfunction in two theoretically separable neurocognitive pathways in adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). ADHD is a common disorder arising in childhood that often results in lifelong educational, social, and occupational impairment. Decades of research has greatly refined our appreciation of the disorder's complexity. To date, no study has managed to identify an effective biological marker, a single neuropsychological test, or a specific genetic profile that accurately identifies persons with ADHD, in part because previous studies have produced inconsistent findings. Many researchers have concluded that this is because the etiology of ADHD is multi-factorial, probably polygenetic in nature, involving numerous small influences on brain function. Consistent evidence points to a hypodopaminergic state in frontostriatal brain regions, hypothesized to result in at least two forms of neurocognitive impairment linked to impulsive ADHD symptoms impaired `executive' performance on tests requiring inhibition of response, and impaired motivation measured by tests assessing insensitivity to delayed reinforcement. Although this model is supported by neuropsychological evidence, functional neuroimaging studies have not yet fully characterized the biological pathology giving rise to these cognitive deficits. It is likely that much of the inconsistency in previous ADHD neurocognitive research results from examining samples with heterogeneous pathologies. Understanding the major sources of neurobiological heterogeneity is the most significant step in future research of ADHD, and ultimately will help clinicians better diagnose and treat the disorder. This project seeks to characterize the functional neuroanatomy of these two ADHD neurocognitive impairments by examining the association of neuropsychological profile, mesocortical and mesolimbic brain dysfunction, and candidate gene susceptibilities. Participants will be 130 adolescents diagnosed with Combined-subtype ADHD (DSM 314.01) and 130 demographically-matched healthy controls. All participants will undergo rigorous psychiatric evaluation, neuropsychological assessment of several different cognitive domains, fMRI measurement of response inhibition and reward system brain activity, and genotyping DAT1, DRD4, plus several other dopamine-related genetic markers previously linked to ADHD. These data will allow us to validate the presence of two separate brain function pathologies in ADHD and to clarify relationships among disordered brain function, cognitive performance and genotype. The planned project is highly collaborative between experts in functional neuroimaging, cognitive testing, clinical assessment and psychiatric genetics. The neurobiological basis of Attention-Deficit/Hyperactivity Disorder is poorly understood because a single reliable biomarker or definitive test for the disorder has yet to be identified. There is evidence from cognitive studies of ADHD youth that impulsive behavior may arise from two markedly different types of neurobiological dysfunction. This project will use functional magnetic resonance imaging (fMRI) to link these two profiles of abnormal brain function in ADHD adolescents to specific types of neuropsychological dysfunction and to certain genetic markers, providing support for the clinical use of these tools to more precisely diagnose biologically-meaningful subtypes of ADHD. PUBLIC HEALTH RELEVANCE: The neurobiological basis of Attention-Deficit/Hyperactivity Disorder is poorly understood because a single reliable biomarker or definitive test for the disorder has yet to be identified. There is evidence from cognitive studies of ADHD youth that impulsive behavior may arise from two markedly different types of neurobiological dysfunction. This project will use functional magnetic resonance imaging (fMRI) to link these two profiles of abnormal brain function in ADHD adolescents to specific types of neuropsychological dysfunction and to certain genetic markers, providing support for the clinical use of these tools to more precisely diagnose biologically-meaningful subtypes of ADHD. [unreadable] [unreadable] [unreadable]